Due to the easy access, large surface area, application dynamics and the non-invasive nature of the treatment, continuous topical administration has been considered to be a superior mode of drug delivery regardless of whether the bioavailability desired is systemic or dermal, regional or localized. Topical drug delivery provides many advantages over other methods of drug delivery, including the ability to bypass the hepatic "first-pass" elimination and metabolism, elimination of gastrointestinal tract irritation, avoidance of the variation in rates of absorption associated with orally administered drugs and the ability to treat conditions which are local in nature both locally and systemically using the same delivery regimen.
A major challenge in developing topical drug delivery systems has been achieving drug absorption in a reproducible manner and in sufficient quantities to exert a therapeutic effect. The absorption rate of topically applied drugs is generally much slower than that through the gastrointestinal tract. In order to overcome the low bioavailability, improved delivery of drugs has been the subject of worldwide pharmaceutical research for many years. Much of the recent research has focused on methods for enhancing the absorption or penetration of drugs.
Chemical methods of enhancing topical absorption of drugs have received considerable attention and efforts in recent years. Some examples of amphoteric molecules that have been investigated for their penetration-enhancing properties include sodium lauryl sulfate (Dugard, P. H. and Sheuplein, R. J., "Effects of Ionic Surfactants on the Permeability of Human Epidermis: An Electrometric Study," J. Ivest. Dermatol., V.60, pp. 263-69, 1973), lauryl amine oxide (Johnson et. al., U.S. Pat. No. 4,411,893), azone (Rajadhyaksha, U.S. Pat. Nos. 4,405,616 and 3,989,816) and decylmethyl sulfoxide (Sekura, D. L. and Scala, J., "The Percutaneous Absorption of Alkylmethyl Sulfides," Pharmacology of the Skin, Advances In Biolocy of Skin, (Appleton-Century Craft) V. 12, pp. 257-69, 1972). It has been observed that increasing the polarity of the head group in amphoteric molecules increases their penetration-enhancing properties but at the expense of increasing their skin irritating properties (Cooper, E. R. and Berner, B., "Interaction of Surfactants with Epidermal Tissues: Physiochemical Aspects," Surfactant Science Series, V. 16, Reiger, M. M. ed. (Marcel Dekker, Inc.) pp. 195-210, 1987).
A second class of chemical enhancers are generally referred to as co-solvents. These materials are absorbed topically relatively easily, and, by a variety of mechanisms, achieve permeation enhancement for some drugs. Ethanol (Gale et. al., U.S. Pat. No. 4,615,699 and Campbell et. al., U.S. Pat. Nos. 4,460,372 and 4,379,454), dimethyl sulfoxide (Herschler, U.S. Pat. Nos. 3,740,420 and 3,743,727, and Sandbourn, U.S. Pat. No. 4,575,515), and nitroglycerine (Leslie et. al., U.S. Pat. No. 4,322,433) are a few examples of compounds which have shown an ability to enhance the absorption of various compounds. Also, combinations of enhancers (co-solvent and amphoteric compounds) have been claimed to enhance penetration in some patents (Saito et. al., U.S. Pat. No. 4,590,190 and Cooper et. al., U.S. Pat. Nos. 4,537,776 and 4,552,872). However, since they penetrate the skin, there are serious questions regarding their toxicity and irritation during chronic use.
Since its discovery in the 1920's, vitamin E has been the subject of heated controversy and extensive research. Over the past 25 years there have been a large volume of studies which provide impressive evidence of the need for vitamin E in maintaining normal body metabolism and in the prevention of deficiency diseases.
The most specific biochemical function of vitamin E is as an in vivo anti-oxidant, protecting cell membranes from the damaging effects of free radicals. Vitamin E has also been shown to protect animals against the damaging effects of nitrogen dioxide and ozone, major air pollutants known to lead to free radical formation in the body. Vitamin E has been found to be effective against the toxic effects of mercury, lead and drugs such as adriamycin and nitrofurantoin, to enhance antibody formation, chemotaxis and phagocytosis of polymorphonuclear leukocytes. The effects of vitamin E on cancer are also being evaluated.
In topical applications, most claims for vitamin E have been as a natural moisturizer to relieve dry skin and indirectly to aid in the concealment of wrinkles and facial lines perceived as characteristics of aging. However, other effects for topically applied vitamin E have been the subject of extensive studies. In the treatment of chronic skin diseases (Nikolowski, W., "Vitamin E Dermatology," Vitamins, No. 3, 1973), reduction in erythema and swelling (Kamimara, M., "Anti-Inflammatory Activity of Vitamin E," J. Vitaminol., V. 18, pp. 201-09, 1972) and wound healing (Ehrlich, M., Traver, H. and Hunt, T., "Inhibitory Effects of Vitamin E in Collagen Synthesis and Wound Repair," Ann. of Surgery, V. 175 (2), Feb. 1972), vitamin E's therapeutic value has been noted.
Vitamin E'S use in cosmetics has also gone well beyond mere moisturization. Although vitamin E has no sun protection factor to speak of, it does provide protection from ultra violet light by scavenging any free radicals generated by the skin during exposure, thereby suggesting a strong rationale for incorporating the vitamin into suncare preparations. Vitamin E also prevents the formation of nitrosamines, which can be formed from nitrite contaminants present in cosmetics containing amines or amides (Mergens, W. and DeRiter, E., "Nitrosamines in Cosmetics," Cos. Tech., Jan. 1980 and Dunnett, P. C. and Telling, G. M., "Study on the Fate of Bronopol and the Effects of Anti-Oxidants on Nitrosamine Formation in Shampoos and Skin Creams," Int. J. Cos. Sci., V. 6, pp. 241-47, 1984.)
Topical use of drugs and cosmetics containing vitamin E poses little risk. Examination of the literature reveals that vitamin E is widely prescribed in dosages ranging from 200 to 2,000 IU for oral use (Bieri, J. G. et. al., "Medical Uses of Vitamin E," N. Engl. J. Med., V. 308, pp. 1063-71, 1983).
Despite the considerable body of research on vitamin E, there has been no appreciation of its potential to enhance the effects of cosmetic and/or pharmaceutically-active agents.